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Genetically humanized mice for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging as promising in vivo models for improved prediction of the pharmacokinetic, drug–drug interaction, and safety characteristics of compounds in humans. This is an overview on the genetically humanized and chimeric liver-humanized mouse models, which are illustrated with examples of their utility in drug metabolism and toxicity studies. The models are compared to give guidance for selection of the most appropriate model by highlighting advantages and disadvantages to be carefully considered when used for studies in drug discovery and development.
Three amperometric biosensors have been developed for the detection of L-malic acid, fumaric acid, and L -aspartic acid, all based on the combination of a malate-specific dehydrogenase (MDH, EC 1.1.1.37) and diaphorase (DIA, EC 1.8.1.4). The stepwise expansion of the malate platform with the enzymes fumarate hydratase (FH, EC 4.2.1.2) and aspartate ammonia-lyase (ASPA, EC 4.3.1.1) resulted in multi-enzyme reaction cascades and, thus, augmentation of the substrate spectrum of the sensors. Electrochemical measurements were carried out in presence of the cofactor β-nicotinamide adenine dinucleotide (NAD+) and the redox mediator hexacyanoferrate (III) (HCFIII). The amperometric detection is mediated by oxidation of hexacyanoferrate (II) (HCFII) at an applied potential of + 0.3 V vs. Ag/AgCl. For each biosensor, optimum working conditions were defined by adjustment of cofactor concentrations, buffer pH, and immobilization procedure. Under these improved conditions, amperometric responses were linear up to 3.0 mM for L-malate and fumarate, respectively, with a corresponding sensitivity of 0.7 μA mM−1 (L-malate biosensor) and 0.4 μA mM−1 (fumarate biosensor). The L-aspartate detection system displayed a linear range of 1.0–10.0 mM with a sensitivity of 0.09 μA mM−1. The sensor characteristics suggest that the developed platform provides a promising method for the detection and differentiation of the three substrates.
Analysis Of Base Isolated Liquid Storage Tanks With 3D Fsi-Analysis As Well As Simplified Approaches
(2017)
Tanks are preferably designed, for cost-saving reasons, as circular, cylindrical, thin-walled shells. In case of seismic excitation, these constructions are highly vulnerable to stability failures. An earthquake-resistant design of rigidly supported tanks for high seismic loading demands, however, uneconomic wall thicknesses. A cost-effective alternative can be provided by base isolation systems. In this paper, a simplified seismic design procedure for base isolated tanks is introduced, by appropriately modifying the standard mechanical model for flexible, rigidly supported tanks. The non-linear behavior of conventional base isolation systems becomes an integral part of a proposed simplified process, which enables
the assessment of the reduced hydrodynamic forces acting on the tank walls and the corresponding stress distribution. The impulsive and convective actions of the liquid are taken into account. The validity of this approach is evaluated by
employing a non-linear fluid-structure interaction algorithm of finite element method. Special focus is placed on the boundary conditions imposed from the base isolation and the resulting hydrodynamic pressures. Both horizontal and vertical
component of ground motion are considered in order to study the principal effects of the base isolation on the pressure distribution of the tank walls. The induced rocking effects associated with elastomeric bearings are discussed. The results
manifest that base isolated tanks can be designed for seismic loads by means of the proposed procedure with sufficient accuracy, allowing to dispense with numerically expensive techniques.
Multi-dimensional fragility analysis of a RC building with components using response surface method
(2017)
Conventional fragility curves describe the vulnerability of the main structure under external hazards. However, in complex structures such as nuclear power plants, the safety or the risk depends also on the components associated with a system. The classical fault tree analysis gives an overall view of the failure and contains several subsystems to the main event, however, the interactions in the subsystems are not well represented. In order to represent the interaction of the components, a method suggested by Cimellaro et al. (2006) using multidimensional performance limit state functions to obtain the system fragility curves is adopted. This approach gives the possibility of deriving the cumulative fragility taking into account the interaction of the response of different components. In this paper, this approach is used to evaluate seismic risk of a representative electrical building infrastructure, including the component, of a nuclear power plant. A simplified model of the structure, with nonlinear material behavior is employed for the analysis in Abaqus©. The input variables considered are the material parameters, boundary conditions and the seismic input. The variability of the seismic input is obtained from selected ground motion time histories of spectrum compatible synthetic ccelerograms. Unlike the usual Monte Carlo methods used for the probabilistic analysis of the structure, a computationally effective response surface method is used. This method reduces the computational effort of the calculations by reducing the required
number of samples.
The LAPS (light-addressable potentiometric sensor) platform is one of the most attractive approaches for chemical and biological sensing with many applications ranging from pH and ion/analyte concentration measurements up to cell metabolism detection and chemical imaging. However, although it is generally accepted that LAPS measurements are spatially resolved, the light-addressability feature of LAPS devices has not been discussed in detail so far. In this work, an extended electrical equivalent-circuit model of the LAPS has been presented, which takes into account possible cross-talk effects due to the capacitive coupling of the non-illuminated region. A shunting effect of the non-illuminated area on the measured photocurrent and addressability of LAPS devices has been studied. It has been shown, that the measured photocurrent will be determined not only by the local interfacial potential in the illuminated region but also by possible interfacial potential changes in the non-illuminated region, yielding cross-talk effects. These findings were supported by the experimental investigations of a penicillin-sensitive multi-spot LAPS and a metal-insulator-semiconductor LAPS as model systems.
The coupling of charged molecules, nanoparticles, and more generally, inorganic/organic nanohybrids with semiconductor field-effect devices based on an electrolyte–insulator–semiconductor (EIS) system represents a very promising strategy for the active tuning of electrochemical properties of these devices and, thus, opening new opportunities for label-free biosensing by the intrinsic charge of molecules. The simplest field-effect sensor is a capacitive EIS sensor, which represents a (bio-)chemically sensitive capacitor. In this chapter, selected examples of recent developments in the field of label-free biosensing using nanomaterial-modified capacitive EIS sensors are summarized. In the first part, we present applications of EIS sensors modified with negatively charged gold nanoparticles for the label-free electrostatic detection of positively charged small proteins and macromolecules, for monitoring the layer-by-layer formation of oppositely charged polyelectrolyte (PE) multilayers as well as for the development of an enzyme-based biomolecular logic gate. In the second part, examples of a label-free detection by means of EIS sensors modified with a positively charged weak PE layer are demonstrated. These include electrical detection of on-chip and in-solution hybridized DNA (deoxyribonucleic acid) as well as an EIS sensor with pH-responsive weak PE/enzyme multilayers for enhanced field-effect biosensing.
The immobilization of NAD+-dependent dehydrogenases, in combination with a diaphorase, enables the facile development of multiparametric sensing devices. In this work, an amperometric biosensor array for simultaneous determination of ethanol, formate, d- and l-lactate is presented. Enzyme immobilization on platinum thin-film electrodes was realized by chemical cross-linking with glutaraldehyde. The optimization of the sensor performance was investigated with regard to enzyme loading, glutaraldehyde concentration, pH, cofactor concentration and temperature. Under optimal working conditions (potassium phosphate buffer with pH 7.5, 2.5 mmol L-1 NAD+, 2.0 mmol L-1 ferricyanide, 25 °C and 0.4% glutaraldehyde) the linear working range and sensitivity of the four sensor elements was improved. Simultaneous and cross-talk free measurements of four different metabolic parameters were performed successfully. The reliable analytical performance of the biosensor array was demonstrated by application in a clarified sample of inoculum sludge. Thereby, a promising approach for on-site monitoring of fermentation processes is provided.
Towards inclusion of the freight rail system in the industrial internet of things - Wagon 4.0
(2017)
Analysis of Big Data Streams to obtain Braking Reliability Information for Train Protection systems
(2017)
The scientific interest in near-Earth asteroids (NEAs) and the classification of some of those as potentially hazardous asteroid for the Earth stipulated the interest in NEA exploration. Close-up observations of these objects will increase drastically our knowledge about the overall NEA population. For this reason, a multiple NEA rendezvous mission through solar sailing is investigated, taking advantage of the propellantless nature of this groundbreaking propulsion technology. Considering a spacecraft based on the DLR/ESA Gossamer technology, this work focuses on the search of possible sequences of NEA encounters. The effectiveness of this approach is demonstrated through a number of fully-optimized trajectories. The results show that it is possible to visit five NEAs within 10 years with near-term solar-sail technology. Moreover, a study on a reduced NEA database demonstrates the reliability of the approach used, showing that 58% of the sequences found with an approximated trajectory model can be converted into real solar-sail trajectories. Lastly, this second study shows the effectiveness of the proposed automatic optimization algorithm, which is able to find solutions for a large number of mission scenarios without any input required from the user.